Field of Endeavor
The present invention relates to creatine derivatives and methods for uses thereof. More particularly, the invention relates to creatine derivatives soluble in aqueous solutions such as acetylated creatine species in the form of acetyl creatine, N-acyl creatines, N,N-diacyl creatines, acetyl creatyl peptides and their aliphatic esters with enhanced solubility that are more bioavailable than any other existing creatine derivative.
Background Information
Many nutritional supplements are available at various retail outlets, in many different delivery and dosage forms, including, but not entirely limited to tablets, capsules, powders, packets, and various other liquids formats including beverages emulsions, concentrates, and shots intended for human consumption.
One nutritional supplement is creatine, whose International Union of Pure and Applied Chemistry (IUPAC) name is 2-(carbamimidoyl-methyl-amino) acetic acid, (Chemical Abstract Services (CAS) No. 57-00-1). Creatine occurs naturally in muscle and brain, and is believed to be an essential component in energy-producing metabolism and normal muscle function and growth, and plays a pivotal role in the storage of phosphate-bound energy in the brain. It is also believed by many to be useful to bodybuilders and other athletes desiring to increase strength, increase muscle mass and/or improve performance.
In a thorough scientific review published in the Journal of Strength and Conditioning, scientists looked at 22 published studies. The average increase in muscle strength following creatine supplementation plus resistance training was 8% greater than the average increase in muscle strength following placebo ingestion during resistance training (20% vs. 12%). Also, the average increase in weightlifting performance (maximal repetitions at a given percent of maximal strength) following creatine supplementation plus resistance training was 14% greater than the average increase in weightlifting performance following placebo ingestion during resistance training (26% vs. 12%). The increase in bench press 1 RM (one rep maximum lift) ranged from 3% to 45%, and the improvement in weightlifting performance in the bench press ranged from 16% to 43%.
In another study, scientists tested the hypothesis to evaluate if five grams of oral creatine supplementation taken daily for six weeks would enhance intelligence test scores and working memory performance in 45 young adult, vegetarian subjects in a double-blind, placebo-controlled, cross-over design. Creatine supplementation had a significant positive effect on both working memory (backward digit span) and intelligence (Raven's Advanced Progressive Matrices), both tasks that require speed of processing.
Creatine supplementation has be shown to have neuroprotective effects in neurological diseases such as Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Another investigation found that five grams of creatine supplementation daily coupled with resistance training (3 times per week for 15 weeks) improved physical function in a 26-year-old man with myasthenia gravis. This individual had a 7% increase in body weight, 4% increase in fat free mass, and improved peak strength up to 37%. Another investigation found that creatine supplementation improves skeletal muscle function in patients with McArdle disease.
Red meat and fish contain about two grams to five grams of creatine per pound. One study compared the effects of consuming two grams of creatine in 250-300 mL of cold water versus two grams of creatine obtained from 0.9 lbs of meat. According to the study, two grams of creatine in solution caused a quicker and greater rise in blood creatine levels, but a quicker drop also. On the other hand, eating meat caused a less dramatic rise but the increase was sustained for a longer period of time. In fact, when they compared the net increase in blood creatine, there was no difference.
Persons with Parkinson disease (PD) exhibit decreased muscular fitness including decreased muscle mass, muscle strength, and increased fatigability. Twenty patients with idiopathic PD were randomized to receive creatine monohydrate supplementation plus resistance training (CRE) or placebo (lactose monohydrate) plus resistance training (PLA), using a double-blind procedure. Creatine and placebo supplementation consisted of 20 grams per day for the first 5 days and 5 grams/day thereafter. Both groups participated in progressive resistance training (24 sessions, 2 times per week, 1 set of 8-12 repetitions, 9 exercises). They discovered that chest press strength and biceps curl strength improvement was significantly greater for the creatine supplemented group.
Short term (5 days), medium term (9 weeks) and long term (up to 5 years) oral creatine supplementation has been studied in small cohorts of athletes whose kidney function was monitored and scientists did not find any adverse effects on renal function.
Another investigation examined over a 21-month period, 98 Division IA college football players who consumed in an open label manner creatine or non-creatine containing supplements following training sessions. Subjects who ingested creatine were administered 15.75 grams/day of creatine monohydrate for five days and an average of 5 grams/day thereafter in 5-10 gram/day doses. According to this study, “long-term creatine supplementation (up to 21-months) does not appear to adversely effect markers of health status in athletes undergoing intense training in comparison to athletes who do not take creatine.”
According to the position stand [?] published by the International Society of Sports Nutrition, creatine is the most effective ergogenic nutritional supplement currently available to athletes in terms of increasing high-intensity exercise capacity and lean body mass during training. Also, supplementation is not only safe, but possibly beneficial in regard to preventing injury and/or management of select medical conditions when taken within recommended guidelines. Further, there is no scientific evidence that the short or long-term use of creatine has any detrimental effects on otherwise healthy individuals. In fact, five days of creatine supplementation enhances the dynamic strength and may increase anaerobic metabolism in the lower extremity muscles, and improves performance in consecutive maximal swims in highly trained adolescent (mean age 16) fin swimmers. There are also data concerning the short and long-term therapeutic benefit of creatine supplementation in children and adults with gyrate atrophy (a result of the inborn error of metabolism with ornithine delta-aminotransferase activity), muscular dystrophy (facioscapulohumeral dystrophy, Becker dystrophy, Duchenne dystrophy and sarcoglycan deficient limb girdle muscular dystrophy), McArdle's disease, Huntington's disease and mitochondria-related diseases. Hypoxia and energy related brain pathologies (brain trauma, cerebral ischemia, prematurity) might benefit from creatine supplementation. Creatine supplementation has also been shown to lead to an improvement in various cognitive tasks.
While we exercise (more specifically intense resistance exercise) muscle mass is built by increasing mTOR (mechanistic Target of Rapamycin) and protein synthesis is enhanced as depicted in the diagram of page 8.
It is also known that certain amino acids such as leucine, isoleucine and creatine amplify the muscle building effect of resistance exercise by some of the same pathways and mechanisms and exercise.
Research shows that ordinary creatine can block 60% of myostatin in muscle, and that both leucine and creatine also activate mTOR while isoleucine plays an additive or potentially synergistic role by increasing insulin sensitivity. Isoleucine is generally overlooked in the muscle building process and given far less priority and recognition than leucine, as evidence by the BCAA formulae in the nutrition marketplace that contain and promote 2:1:1, 4:1:1, and even 8:1:1 ratios of leucine to isoleucine to valine. However, far greater value is placed on isoleucine in these inventions due to its ability to allow the body to more efficiently use insulin because of its ability to activate mTOR and because insulin is the most anabolic of all hormones including both testosterone and HGH (human growth hormone) in the human body.
It should be realized from the foregoing description that an additive and/or synergistic effect is achieved by administering to mammals adequate doses of each of the forms of creatine described herein. The serving may contain one or more of the creatine species each species or combinations thereof contributing significantly to muscle growth.
Di-Peptide Superiority.
It is well known that chain length has an effect on the absorption of biologically active peptides from the GI tract. Furthermore, we know that the potency of orally consumed peptides decreases as the chain length increases. Di-peptides and tri-peptides, but not free amino acids, are more potent than peptides with more than three amino-acids residues.
Administration of the di-peptide Leucine-IsoLeucine can increase translocation of GLU-4 to the plasma membrane. Moreover, these di- and tri-peptides have a better absorption than free amino acids. Studies also suggest that the insulin stimulates dipeptide transport and that leucine is an insulin-mimetic amino acid as well as having certain qualities of insulin like activating mTOR independent of insulin. Isoleucine is believed to enhance these processes because of an additive or synergistic effect for its ability to make insulin work better by decreasing insulin resistance and increasing insulin sensitivity.
The peptide amino acid transporter Pept-1, located in the intestinal brush border membrane, provides a potent mechanism for protein absorption in the human intestine. Studies have shown that Pept-1 transports dipeptides and tripeptides but not free amino acids or peptides with chain lengths greater than three amino acids. Conversely, these di-peptides designed to both ignite mTOR and inhibit a large percentage of myostatin for explosive muscle growth and potentially improve brain health.
Cognitive Creatine
The use of creatine to enhance muscle and performance for athletes, bodybuilders and other fitness enthusiasts is well known within these communities. However, creatine's role in brain health and the exceptional cognitive benefits it offers are not well known to the general public and/or to persons in the athletic community. No matter what sport you play having a sharper mind is critical to superior athletic performance at any level. In any sport you have to think and react superfast to achieve success. Creatine is unique in that it enhances both mind and muscle.
It is well known that molecules such as glucose and creatine provide energy for the brain. ATP (adenosine tri-phosphate) provides energy for cognitive function. In fact, cognitive function is completely dependent on ATP. We also know that persons with creatine transport deficiencies have impaired brain function. These persons experience dementia because creatine does not cross the BBB (blood brain barrier). We are also aware that the hippocampus exhibits the most profound neurological benefit from creatine, but is also highly susceptible to degenerative damage like that observed with aging. Science dictates that creatine is necessary for a healthy brain and to slow aging. The bigger picture here is that creatyl peptides with an added fatty acid ester side chain have the potential to readily cross the BBB. For these reasons these new super creatine peptides could be the next big breakthrough in regard to pharmaceutical smart drugs and also have the potential to retard and even reverse aging.
Research shows that both vegetarians (this population does not consume animal proteins that contain significant amounts of creatine) and elderly persons given creatine showed significant improvement in intelligence, IQ scores and improved ability to repeat longer sequences of numbers from memory.
The brain needs creatine. Creatine deficiency in the brain results in mental retardation. There is something known as creatine transporter deficiency which is caused by an impairment of the SLC6A8 creatine transporter. When SLC6A8 stops working creatine can no longer penetrate the brain. However, adding a long chain fatty ester to a creatine allows creatine to penetrate into neuronal cells in the brain even when no SLC6A8 is available. One study even showed that a specific dodecyl creatine ester resulted in a 20 fold increase in human fibroblasts compared with the endogenous creatine content.
Thus, creatine is known to provide many benefits, including enhancing athletic performance in the strength-power sports, promoting gains in lean body mass and muscle fiber hypertrophy (growth), helping neuromuscular function in those with various metabolic diseases, improving memory, assisting various neural functions. Further, creatine has long-term safety data.
Creatine is typically offered in tablet, capsule and powder form; however, powder is currently form is most common form of creatine sold in retain stores. More recently, U.S. Pat. No. 8,445,466 was granted giving birth to the first aqueous stable carbonated creatyl (creatine) beverage which is now also for sale in the world's largest health food store retailers. However, most forms of creatine and all its derivatives suffer from either very low solubility and/or other problems. For example creatine HCl, can cause potential problems to the teeth, mouth and esophagus because of its high acid content. Another example of a creatine that suffers from very poor solubility (which, ironically, is by far the most popular of all creatine varieties) is creatine monohydrate. Solubility is a rate-limiting factor of bioavailability. Since drugs and/or nutrients must be soluble to achieve Gastro Intestinal Tract (GIT) absorption, the majority of drug modification and formulation strategies focus on improving solubility. The higher the concentration of drug in solution, and the longer the drug stays in solution as it travels through the GIT, the higher the absorption and bioavailability.
A drug's solubility/rate-of-dissolution is often related to its in vivo performance (bioavailability). Therefore, prediction and measurement of these properties becomes critical in characterizing new drug candidates and the formulations in which they are developed. The establishment and understanding of IVIVC's (in-vitro-in-vivo correlations) of drug candidates formulated into dosage forms begins with measurement of the drug's solubility and dissolution rate.